The quest for a complete understanding of mixtures is a challenge which has stimulated the development of several techniques. One of the most powerful NMR-based techniques is known as Diffusion-Ordered SpectroscopY (DOSY), in which it is possible to distinguish the NMR spectra of chemical species with different hydrodynamic radii, i.e. with different self-diffusion coefficients. It allows the study of intact mixtures, providing information on the interactions within the mixture and saving time and money compared to other techniques. Unfortunately, DOSY is not very effective when signals overlap and/or the diffusion coefficients are very similar. This drawback has led to the development of new methods to overcome this problem. The present investigation is focused on developing some of these. Most DOSY datasets show multiplet phase distortions caused by J-modulation. These distortions not only hinder the interpretation of spectra, but also increase the overlap between signals. The addition of a 45º purging pulse immediately before the onset of acquisition is proposed as a way to remove the unwanted distortions. Most DOSY experiments use 1H detection, because of the higher sensitivity which is generally achieved. However, acquiring spectra with other nuclei such as 13C can reduce overlap problems. Two new sequences have been developed to maximize the sensitivity of heteronuclear DOSY experiments. In order to increase resolving power, it is also possible to incorporate another variable into diffusion experiments as a further dimension. If this results in an approximately trilinear dataset (each dimension varying independently), it is possible to extract physically meaningful information for each component using multivariate statistical methods. This is explored for the cases where the new variable is either the relaxation behaviour or the concentration variation (which can be measured during a reaction or in a set of samples with different concentrations for each component). PARAllel FACtor (PARAFAC) analysis can obtain the spectra, diffusional decay and relaxation evolution or kinetics for each of the components. In a completely different approach, the separation power of liquid chromatography has been combined in a novel way with the NMR potential for elucidating structures. NMR has been used previously as a precise way to measure average flow velocities, even in porous media. Using this capability to detect the different average velocities of solutes that occur in chromatographic columns ought to provide a new way of analysing mixtures with the same potential as LC-NMR, but faster and more simple. In such a flow system, a chromatographic column is introduced into the NMR probe and a 2D dataset is acquired and Fourier transformed to obtain the velocity distribution for each of the detected NMR signals.

Pendant ma thèse de doctorat, j’ai eu la grande chance de travailler sur le développement de nouvelles méthodes de deux techniques spectroscopiques complétement différentes : la Résonance Magnétique Nucléaire (RMN) et la Spectroscopie de Masse par Résonance Cyclotronique Ionique à Transformée de Fourier (FT-ICR/MS). En tant que méthodologiste, mon but principal a été d’améliorer les méthodes existantes et la théorie. En RMN, l’outil fantastique de la manipulation des spins permet la mise en place des séquences d’impulsions, et en FT-ICR, les rapports masse sur charge (m/z) des ions et des fragments d’ions obtenus par différents chemins de fragmentation peuvent être appliqués à des problèmes en chimie, biochimie et médecine. Le manuscrit de ma thèse de doctorat comporte deux parties. Les sujets abordés étant différents, ce manuscrit a été rédigé pour que chaque chapitre puisse être lu indépendamment. La première partie aborde la RMN dans le chapitre I. Dans ce chapitre, nous avons amélioré une méthode développée précédemment dans l’equipe pour l’étude de l’échange rapide des protons par RMN. Nous avons adapté la méthode à l’étude de l’acide aminé histidine, système en apparence simple mais qui s’est avéré très compliqué à l’étude. La deuxième partie de ma thèse de doctorat aborde la spectroscopie de masse et comprend deux chapitres. Dans le chapitre II, nous avons essayé de faire revivre et de mettre en œuvre une méthode longtemps oubliée ; il s’agit de la méthode d’isolement d’ions par éjection sélective (‘notch ejection’) par spectroscopie de masse FT-ICR. Un autre sujet abordé pendant ma thèse, qui est décrit dans le chapitre III, concerne l’utilisation de trois impulsions rf dans une expérience à deux dimensions (2D) ICR. Notre objectif a été de mieux comprendre la complexité du comportement des ions pendant cette expérience 2D ICR, en particulier pour le cas d’impulsions courtes. / This thesis encompasses methodological developments in both nuclear magnetic resonance and Fourier transform ion cyclotron resonance mass spectrometry. The NMR section explores the effects of scalar relaxation on a coupled nucleus to measure fast exchange rates. In order to quantify these rates accurately, a precise knowledge of the chemical shifts of the labile protons and of the scalar couplings is normally required. We applied the method to histidine where no such information was available a priori, neither about the proton chemical shifts nor about the one-bond scalar coupling constants J(1H15N), since the protons were invisible due to fast exchange. We have measured the exchange rates of the protons of the imidazole ring and of amino protons in histidine by indirect detection via 15N. Not only the exchange rate constants, but also the elusive chemical shifts of the protons and the coupling constants could be determined. For the mass spectrometry section, the ion isolation project was initiated to study the effect of phase change of radiofrequency pulses. Excitation of ions in the ICR cell is a linear process, so that the pulse voltage required for ejecting ions must be inversely proportional to the pulse duration. A continuous sweep pulse propels the ion to a higher radius, whereas a phase reversal causes the ion to come to the centre. This represents the principle of ‘notch ejection’, wherein the ion for which the phase is reversed is retained in the ICR cell, while the remaining ions are ejected. The manuscript also contains a theoretical chapter, wherein the ion trajectories are plotted by solving the Lorentzian equation for the three-pulse scheme used for two-dimensional ICR. Through our simulations we mapped the ion trajectories for different pulse durations and for different phase relations.

Abstract The subject of this thesis is flow imaging by methods based on the nuclear magnetic resonance (NMR) phenomenon. The thesis consists of three related topics: In the first one the feasibility of measuring velocity maps and distributions inside a microfluidic device by pulsed field gradient (PFG) NMR has been demonstrated. The second topic was to investigate microfluidic gas flow using a combination of a special detection technique and a powerful signal enhancement method. The third topic is related to the unambiguous determination of velocities under challenging experimental conditions and introduces a new, improved velocity imaging sequence. In the first part, well established imaging methods have been used to study water flow inside a micromixer. A surface coil matching the region of interest of the mixer was home built and used in the measurements in order to gain a better signal-to-noise ratio. Velocities inside the mixer have been measured by phase-encoding velocity, with unprecedented spatial resolution. Two dimensional NMR imaging and velocity maps revealed clogging and different manufacturing qualities of the mixers. In addition to the velocity maps, which display an average velocity for spins within one pixel, complete velocity distributions (so called average propagators) were measured. It was found that in the absence of spatial resolution in the third dimension, the propagator data can provide valuable insight to the flow system by revealing overlapping flow passages. The next topic was gas flow inside a microfluidic device. It was investigated by time-of-flight flow imaging. The measurement of the weak gas signal was enabled by the use of two signal enhancement techniques: remote detection NMR and parahydrogen induced polarization (PHIP). The results demonstrate that a very significant signal enhancement can be achieved by this technique. In the future it may enable the investigation of interesting chemical reactions inside microreactors. The third and last topic of the thesis deals with measuring flow by the so called multiecho sequences. When multiecho sequences are used in combination with phase encoding velocity, an error may be introduced: the multiecho sequence may produce a cumulative error to the phase of the magnetization, if it is sensitive to RF pulse imperfections. The problem has been elaborately explained and various solutions discussed, among the newly proposed one. Experimental results demonstrate the performance of the new velocity imaging sequence and show that the new sequence enables the unambiguous determination of velocities even in challenging experimental conditions resulting from inhomogeneous radio frequency fields of the measurement coils.

Abstract Xenon atoms and sulfur hexafluoride (SF6) molecules can be dissolved in liquids and liquid crystals or adsorbed in porous materials. Nuclear magnetic resonance (NMR) spectra of 129Xe or 19F nuclei reveal information about their surroundings. This means that xenon atoms and SF6 molecules can be used as probes to indirectly study materials by NMR spectroscopy. The change in the spectra arises from a NMR interaction called shielding. Especially in the case of xenon, shielding reveals even the slightest changes, for example, in the density of a liquid it is dissolved in. Because a change in temperature leads to a change in the density of the liquid as well, temperature change is observed as a shift of the resonance line in the 129Xe NMR spectrum. This property can be utilized in the accurate determination of the sample temperature. Self-diffusion measurements of the gases provide additional information on a larger scale rather than just the immediate surroundings of atoms or molecules. Various liquid crystals were studied using xenon and SF6 as probes proving their applicability. It is often considered that the signal observed in NMR experiments is very weak and limits the full potential of the method. This is true especially with the samples in gaseous form. The Spin-Exchange Optical Pumping (SEOP) hyperpolarization method solves this problem in the case of xenon. A 129Xe NMR signal can be enhanced by a factor of 104–105 by SEOP and this opens access to techniques that are not otherwise possible. The remote detection technique, which separates the encoding and detection steps of the typical NMR experiment both temporally and spatially, is one of these techniques. The potential of the combination of SEOP and remote detection techniques was shown in studies of thermally modified Pinus Sylvestris.

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A series of 31 sulfur-nitrogen donor ligands and 64 metal(II) complexes have been investigated. The thiomethylated aniline ligands 2–(methylthiomethyl)aniline 2MT and 2–(methylthio)aniline 2MA were synthesized with their substituted derivatives (-Me, -MeO, -Cl, -Br, -NO2) to serve as chelating agents. These ligands behave as bidentate ligands with SN donor group with Co(II), Ni(II) and Cu(II). The Co(II) and Ni(II) complexes have the ML2Cl2 molecular formula while the Cu(II) complexes formed with MLCl2 stoichiometry where L is the bidentate ligand. The ligands and their metal(II) complexes have been characterized by elemental analysis and with spectroscopic techniques. The trend observed in the NMR spectra and IR frequencies of the thiomethylated compounds shows there is a significant difference between the 2MT and 2MA series as a result of sulfur lone pairs extending the conjugation of the aromatic ring in the case of the latter. The effect of the position and electronic nature of ring substituent on the NMR shifts of the amine protons is discussed. The 6- and 5-membered chelate complexes formed by the 2MT and 2MA ligands respectively do not show significant diversity in their spectroscopic properties. From the elemental analysis for the Co(II) and Ni(II) complexes, their compositions reveal 1:2 M:L stoichiometry with 2 chlorine atoms from the respective metal salts. In addition, the spectroscopic data are largely indicative of tetragonally distorted structures for these solid complexes. The X-ray crystallography data reveal the Cu(II) complexes exist as square pyramidal dimers and with long Cu–Cl equitorial bonds fit into the tetragonally distorted octahedral structure. The electrolytic nature of Co(II) and Cu(II) complexes in DMF were found to be similar, they behave as non electrolytes in contrast to Ni(II) complexes which are 1:1 electrolytes. The electronic spectra of these metal(II) complexes were found to be different for both their solid forms and in solutions of DMF and DMSO and this has been discussed. The thiomethylated aniline ligands possess the amine and thioether groups which are present in many known biologically active compounds, hence the biological activity of the ligands and their metal complexes were tested against three strains of bacteria and one fungus. The methoxy-substituted derivatives were found to possess better inhibitory activity and this was similarly reflected in the metal(II) complexes. The activity of the complexes can be said to be in the order, Cu(II) > Co(II) > Ni(II). The Schiff-base derivatives were prepared from the ligands and para-methoxysalicylaldehyde and their Cu(II) complexes were synthesized in order to determine their biological activity. The Schiff-base ligands were found to be less active than their parent ligands. The Cu(II) complexes are not soluble in water, DMSO or DMF, as a result and could not be evaluated for their biological activity. Based on the good results from the antimicrobial evaluation, the antiplasmodial activity of some of the Co(II), Ni(II) and Cu(II) complexes of the thiomethylated ligands against Plasmodium falciparum (FCR-3) was determined. At 50 μM concentration level, the Cu(II) complexes show activity equal or better than the prophylactic chloroquine. The Cu(II) complexes with the methoxy-substituted demonstrated exceptional activity but their Co(II) and Ni(II) analogues did not show any activity. The cytotoxicity of the active Cu(II) complexes at 50 μM concentration was determined against the breast cancer cell line (MDA-MB-231). The compounds destroyed the cancer cell in the range of 28–40%, thus showing their preferred activity against the parasitic cell instead of the cancer cell. The selectivity demonstrated by these compounds have shown them to be potential antimalarial agents and this could be further investigated.

Submitted in partial compliance with the requirements of the Master’s Degree in Technology: Homoeopathy, Durban University of Technology, Durban, South Africa, 2017. / Introduction Hahnemann was adamant that his methodology for LM1 prescription be reproduced exactly, in order to develop the latent medicinal properties of the crude substance reliably (Barthel 1991). Yet quality assurance practices during manufacturing are currently aligned to Good Manufacturing Process, in adherence to Pharmacopeia which permit substantial deviation from the strict quantities and practices (Kayne 2006) prescribed in Hahnemann’s 6th edition Organon (Hahnemann and O'Reilly 2001). Often the equipment, methods and practices favour expedience or utilise new technologies, under an assumption that the remedy produced is unaffected, since the mechanisms underlying the action of homoeopathic remedies are not understood or determined (Barthel 1991). Aim The primary purpose of this study was to compare and evaluate the nuclear magnetic resonance (NMR) spectra of Natrum muriaticum LM1, produced using strict adherence to original Hahnemannian methodology, to samples sourced from a representative variety of sources available to local homoeopathic practitioners, in the medicinal prescription form patients may receive. Additionally, the researcher set out to confirm that these Natrum muriaticum LM1 samples could be shown to produce distinct NMR spectra when compared to a Lactose LM1 control. The final objective was to ascertain whether two samples produced with the same strict adherence to Hahnemannian methodology, from same source materials would yield similar NMR Spectra, distinct from a Lactose LM1 control sample. Methodology The researcher produced an in-house Natrum muriaticum LM1 (0/1) sample in accordance with aphorism 272 of the 6th edition Organon (Hahnemann and O'Reilly 2001). Similarly, a second sample was produced by the DUT Homoeopharmaceutics Senior Lecturer, within the same ambient conditions and protocol. A third sample was produced by a local make-to-order (MTO) company, using the same sodium chloride crude substance sample utilised in the production of the first two samples. These three samples emulate the make-to-order (MTO) options available to homoeopathic practitioners. A fourth sample was obtained ex-stock from highly regarded local supplier (Homoeopathix Trading Company (South Africa)), while the fifth and sixth samples were procured ex-stock from highly regarded suppliers abroad, Helios (United Kingdom) and Roy & Co. (India) respectively. These samples represented the make-to-stock (MTS) sourcing options available to homoeopathic community. The researcher transported the samples to Chemistry Department of the University of Stellenbosch Chemistry Department in Cape Town. Any external influences such as vibration, changes in temperature, electromagnetic disturbances, heat or strong light were avoided or minimised as far as was practical. The six LM1 potency samples were prepared immediately prior to NMR analysis from their respective source materials to a 20% alcohol concentration, as could be done in practice for the patient prescription where the alcohol content would serve as a preservative. Four controls comprised the seventh, eighth, ninth and tenth samples, for comparative analysis and to confirm sample homogeneity. . Lactose (LM1) . Source lactose in solution . Water used in preparation of NMR samples . Ethanol solvent The ten samples were assigned a random reference number by Dr Jaco Brand (Nuclear Magnetic Resonance Unit Manager), to remove bias during NMR analysis. Five samples were drawn from each of the ten randomised samples and labelled, while deuterated dimethyl sulfoxide-d6 (DSMO) contained within a separate capillary tube served as an external lock and reference solvent. The researcher then carried out the analysis under qualified supervision to ensure best-practice was applied throughout. The resulting data (FID) was processed to derive the chemical shift and relative integration values, which were captured into a Microsoft® Excel 2010 spreadsheet to calculate the relative integration values of each sample run. Statistical analysis was performed in GNU PSPP version 085, the data was analysed using descriptive statistics and the non-parametric tests, Kruskal-Wallis and Mann-Whitney U-test (due to small data size and nature of distribution) at a statistical significance interval of α = 0.05. Results Natrum muriaticum LM1 samples sourced from a variety of make-to-order (MTO) and make-to-stock manufacturing environments produced almost universally distinct NMR spectra profiles in terms of chemical shifts and relative integration values of the CH2, CH3 and H2O signals, at an alcohol concentration of 20%, when compared to a Lactose LM1 control sample. When the NMR spectra of make-to-order (MTO) and make-to-stock (MTS) remedies were analysed and compared to each other in terms of chemical shifts and relative integration values of the CH2, CH3 and H2O signals, they were for the most part statistically distinct, but some anomalous results emerged. There was no statically significant difference in NMR spectra in terms of chemical shift, between the two samples produced in the same environment using the methodology to closely aligned to Organon (Hahnemann and O'Reilly 2001), yet in terms of relative integration values, they were statistically distinct. Conclusion The low alcohol percentage associated with the medicinal dosage of LM1 prepared for analysis failed to produce an OH peak on NMR spectra. In addition, it is not possible to identify the variables or indeed account for the nature of NMR spectra that are produced after sample analysis. This study concludes that while NMR was able to discern physico-chemical distinction between LM1 potency Natrum muriaticum remedies to control conclusively, this does not translate to practical application of NMR for quality control or remedy comparison for LM potencies at alcohol content levels, associated with medicinal prescription. / M

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